We herein review the outline of the new 8th TNM classification of lung cancer. The international TNM classification is formulated and revised by the Union for International Cancer Control (UICC). The 8th TNM classification of the lung cancer has been applied to the primary lung cancer since January 2017. The UICC-TNM classification is identical to that defined by the Japan Lung Cancer Society, which was published in "Classification of Lung Cancer, ver. 8", at the same time as the 8th UICC-TNM book. The UICC-TNM classification was prepared by analyzing the database of the International Association for the Study of Lung Cancer (IASLC). The changes from the 7th to the 8th edition are summarized as follows: The T-descriptor of the largest diameter of the tumor was subdivided into 1, 2, 3, 4, 5, and 7 cm; the maximum diameter of the tumor was to be measured using the solid component of the tumor (i.e. the invasive part of the tumor), not the whole tumor including ground-glass opacity; the N classification was not changed; in the M classification, the M1b classification was subdivided into M1b (single metastasis of a single organ outside of the chest) and M1c (multiple extrathoracic metastases); Stage IA was subdivided into Stages IA1, IA2, and IA3; Stage IIIC was newly established; Stage IV was subdivided into Stages IVA and IVB; and the relationship between TNM and Stage has also been partly changed. These changes, issues with the 8th edition, and future perspectives are described in this report.

Among non-small cell lung cancer (NSCLC) patients, those with mediastinal lymph node metastasis are categorized as N2 NSCLC. Before the advent of radiotherapy and chemotherapy, surgical resection including mediastinal lymph node metastasis was actively carried out for N2 NSCLC. In the era of definitive radiotherapy, sequential chemoradiotherapy and concurrent chemoradiotherapy, it has become possible to obtain a cure without surgery. However, the results of chemoradiotherapy have been stagnant, at a 5-year survival rate of 15% to 20%. For years, clinical trials have explored stronger local therapies and systemic treatments. For example, high-dose chemoradiotherapy, the addition of cetuximab (EGFR antibody) or tecemotide (MUC1 peptide vaccine) and the development of novel chemotherapeutic drugs (e.g. pemetrexed, S-1) have been examined for application in treating N2 NSCLC. In addition to improving the treatment outcomes, attempts to decipher the heterogeneity of N2 NSCLC and deliver appropriate local therapy according to the anatomical position of the primary tumor and mediastinal lymph node metastasis have also been under development. In this article, I will provide an overview of the development of treatment strategies for patients with N2 NSCLC.

Objective. We analyzed the efficacy of ceritinib in patients with ALK-rearrangement non-small cell lung cancer (ALK+NSCLC) who had a history of ALK inhibitor (ALKi) therapy including alectinib. Methods. The efficacy and safety of ceritinib in patients with ALK+NSCLC was analyzed in a Japanese phase I study. The efficacy of ceritinib was also analyzed in patients with a history of alectinib therapy in a Japanese phase I study and ASCEND-1. Results. In the Japanese phase I study, the rate of major serious adverse events was increased with ALT. The overall response rate (ORR) and disease control rate (DCR) in patients administered ceritinib 750 mg/day, the maximum tolerated and recommended dose, were 37.5% (3/8) and 75.0% (6/8), respectively. The ORR in patients who had a history of ALKi therapy was 52.9% (9/17, all patients showed a partial response [PR]), and the progression-free survival was longer than 4.2 months in these responders. An ALK secondary mutation (L1196M, I1171, I1171T) was reported in three of the nine patients who showed PR. In the Japanese phase I study and ASCEND-1, PR was confirmed in 41.7% (5/12) of patients who had a history of alectinib therapy. Conclusion. Ceritinib may be a new treatment option for ALK+NSCLC patients with a history of alectinib therapy.

Objective. To evaluate the effectiveness and safety of S-1 monotherapy for lung cancer associated with interstitial pneumonia (IP). Methods. The medical records of 15 patients with lung cancer-associating IP from April 2005 through March 2015 were retrospectively evaluated to determine the clinical response, adverse effects, and frequency of acute respiratory deterioration after S-1 monotherapy. Results. The median age was 73 (range, 64-80) years, the male/female ratio was 13/2, and 14 patients were smokers. The Eastern Cooperative Oncology Group performance status was 0/1/2/3 in 2/5/5/3 patients, respectively. The epidermal growth factor receptor mutation status was positive, negative, and unknown in 1/9/5 patients, respectively. The histopathological type was adenocarcinoma in 8, squamous cell carcinoma in 5, and other in 2 patients. The clinical stage was I/II/IIIA/IIIB/IV/postoperative recurrence in 2, 0, 2, 3, 6, and 2 patients, respectively. S-1 monotherapy was given as first-/second-/third-/fourth-line or later chemotherapy in 3, 1, 4, and 7 patients, respectively. The IP pattern was usual IP in 11 patients and non-usual IP in 4 patients. The median number of S-1 monotherapy cycles was 2 (range, 1-6); each cycle continued for 4 weeks, followed by a 2-week rest period. The median progression-free survival after S-1 monotherapy was 71 (range, 12-293) days, and the median survival time was 329 (range, 24-1291) days. There were no cases of acute respiratory deterioration after S-1 monotherapy. Conclusion. S-1 monotherapy was safe and effective for patients with lung cancer-associating IP, including those with a poor performance status and those who had previously received multiple lines of chemotherapy.

Objective. We investigated the clinical effect of gastric acid-suppressing drugs (ASs) on the efficacy and safety of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR mutations. Methods. The clinical characteristics, efficacy, and toxicity of gefitinib and erlotinib were retrospectively evaluated in 98 patients with EGFR mutation-positive adenocarcinoma who had been treated with gefitinib or erlotinib at our center between August 2008 and December 2014. Results. Among the 56 patients receiving gefitinib, ASs were coadministered in 25 (44.6%): 17 received a proton pump inhibitor, and 8 received a histamine 2 receptor antagonist. Among the 42 patients receiving erlotinib, ASs were coadministered in 33 (78.6%): 21 received a proton pump inhibitor, and 12 received a histamine 2 receptor antagonist. Among the patients receiving gefitinib and erlotinib, the objective response rate, disease control rate, and median progression-free survival were not significantly different between those who did and did not receive ASs. Regarding toxicity, in the erlotinib group, the incidence of Grade 3/4 AST or ALT elevation was significantly lower among patients receiving ASs than among those not receiving ASs (3% vs. 22%; p=0.023). There were no other significant differences in adverse events among the treatment subgroups. Conclusions. These findings suggest that the co-administration of ASs had no effect on the efficacy or toxicity of EGFR-TKIs in patients with EGFR mutation-positive NSCLC.

Background. Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is a rare tumor and accounts for less than 0.5% of all primary lung neoplasms. Case. A 66-year-old woman complaining of a cough and fever was admitted to our hospital. Chest computed tomography (CT) revealed a lung tumor in the left lower lobe and swelling of the left hilar lymph node. CT also revealed consolidation with air bronchogram in the right middle lobe and left lingular segment. The patient was diagnosed with adenocarcinoma using a transbronchial lung biopsy (TBLB), and she underwent surgery for lung cancer (cT1bN1M0, stage IIA). We performed left lower lobectomy, lymphadenectomy, and resection of a lesion that was suspected to be bronchiectasis in the lingular segment. The tumor was diagnosed as acinar adenocarcinoma, pT1aN1M0, stage IIA, while the lesion in the lingular segment was pathologically diagnosed as MALT lymphoma. The patient was not diagnosed with MALT lymphoma following the analysis of a TBLB specimen from the lesion in the right middle lobe after surgery; she underwent a follow-up examination for this lesion. Conclusion. We experienced a case of pulmonary MALT lymphoma that was found after surgery for lung cancer.

Background. Standard surgery for non-small cell lung carcinoma is pulmonary lobectomy with hilar and mediastinal lymphadenectomy; however, there are no standard surgical procedures for interlobar lung cancer. Case. A 73-year-old woman with palpitations and dyspnea was referred to our hospital for the evaluation of an abnormal lesion detected on computed tomography. Bronchoscopy revealed the lesion to be atypical adenomatous hyperplasia, and it was suspected of being lung cancer. The lesion was located between the left upper and lower lobes. Segmentectomy of S¹⁺² and S⁶ was performed thoracoscopically due to obstructive ventilatory impairment (FEV_1.0=1.47 l). A microscopic examination showed the lesion to be an adenocarcinoma with invasion beyond the incomplete fissure. She has had no recurrence for 2 years post-operatively. Conclusion. In rare cases involving interlobar non-small cell lung cancer, segmentectomy might be the preferred surgical procedure.

Background. Pulmonary carcinoid tends to be vascular and demonstrates enhancement. Liver metastases of carcinoid tumor complicated by chronic hepatitis can be particularly difficult to diagnose. Case. A 65-year-old man was diagnosed with hepatitis C in 1990. Tumors were discovered in the right lung and liver during a medical checkup in 2011. Although bronchoscopy was performed for the right lung tumor at hospital A, it did not lead to a diagnosis. The liver tumor was regarded as hepatocellular carcinoma in hospital B because of the underlying disease. Therefore, the liver tumor was treated using transcatheter arterial chemoembolization (TACE). After he had been observed in clinic C, he was referred to our hospital because of a rapid increase in the right lung tumor size in 2013. Although the right lung tumor could not be diagnosed by a lung biopsy, a neuroendocrine tumor was diagnosed by a liver biopsy. Liver metastases of pulmonary carcinoid were diagnosed conclusively based on imaging findings. While carboplatin and etoposide therapy was administered initially, the chemotherapy was discontinued because of liver dysfunction. The patient underwent right middle lobe resection and lymph node dissection because of recurring obstructive pneumonia and TACE for the liver metastases. His general condition gradually worsened, and he died three years after the first visit to our hospital. Conclusion. We experienced a case of pulmonary carcinoid with liver metastases complicated by chronic hepatitis C. We believe that an aggressive liver biopsy without regard to the patient background is important for the definitive diagnosis in such difficult cases.

Background. Osimertinib is generally effective for T790M-positive epidermal growth factor receptor (EGFR) gene-mutant non-small cell lung cancer. Case. A 77-year-old female was diagnosed with lung adenocarcinoma in the lower lobe of the left lung harboring a 15-base-pair deletion in exon 19 (ex19 15-bp del) of the EGFR gene. Another nodule was detected in the right lower lobe. She had received gefitinib as a first-line treatment for two years, which resulted in shrinkage of both lesions. After disease progression occurred during gefitinib administration for one year, afatinib was consequently administered for another year; however, afatinib was also ineffective. A transbronchial re-biopsy for the left primary lesion revealed the existence of ex19 15-bp del and T790M double mutations. Osimertinib induced the clear shrinkage of the primary lesion and no change in the right lung lesion. However, right pleural effusion appeared and progressed, and the findings of the effusion were ex19 15-bp del-positive and T790M-negative. Left hydronephrosis developed two months later, and right hydronephrosis occurred three months after that, thus requiring percutaneous renal pelvis drainage. The patient was lost due to the progression of lung cancer at four months after osimertinib initiation. Conclusion. Treatment with osimertinib can occasionally result in different responses from multiple lesions because of the spatial heterogeneous T790M status of tumor cells in non-small cell lung cancer harboring an EGFR gene mutation.

Background. Pulmonary pleomorphic carcinoma (PPC) is a subtype of sarcomatoid carcinoma with a poor prognosis, and the response to chemotherapy is generally poor. In recent years, the effectiveness of immune checkpoint inhibitors against PPC has been reported. Case. A 61-year-old never-smoking woman was admitted to our hospital with blood sputum. She was diagnosed with PPC (cT2N2M0, stage IIIA) with an EGFR mutation at exon21 L858R. She was treated with chemoradiotherapy, but the tumor became progressive three years and three months after first-line therapy. Therefore, she was treated with gefitinib and then with gefitinib plus pemetrexed for five years. After disease progression occurred again, nivolumab therapy was initiated as fourth-line treatment. She received 12 cycles as maintenance therapy, which resulted in good disease control. Conclusion. We reported a case of advanced PPC with an EGFR mutation in a never-smoker leading to favorable disease control with nivolumab therapy. A study in a larger number of PPC cases is required to confirm the efficiency of nivolumab therapy.

Background. Pulmonary pleomorphic carcinoma (PPC) is a rare tumor of the lung and generally carries a poor prognosis. In addition, cases of PPC complicated by humoral hypercalcemia of malignancy (HHM) with an increased serum level of parathyroid hormone-related protein (PTHrP) produced by the tumor are rare. Case. A 59-year-old male smoker presented to us with a chief complaint of pain extending from the right shoulder to the back. Chest computed tomography (CT) showed an 11-cm mass shadow in the right apex area infiltrating the chest wall and an enlarged left adrenal gland. A CT-guided biopsy showed poorly differentiated tumor cells with sarcomatous changes, which led to the diagnosis of PPC (cT4N0M1b, clinical stage IV, ADR). When admitted for treatment, the patient developed mild consciousness disturbance and was found to have an increased serum level of PTHrP and hypercalcemia; based on these findings, the patient was diagnosed with HHM. He was administered an intravenous infusion of zoledronic acid in saline to control the hypercalcemia. After the serum calcium levels normalized, he was administered six courses of carboplatin+paclitaxel+bevacizumab combination chemotherapy. The chemotherapy proved effective. Conclusion. Although chemotherapy is known to have poor efficacy in patients with advanced PPC, three-drug combination therapy including bevacizumab proved useful in our patient.

Background. Nivolumab, an anti-programmed death-1 specific monoclonal antibody, has become a standard second-line chemotherapy agent for metastatic non-small cell lung cancer (NSCLC). Nivolumab induces several autoimmune adverse events, defined as immune-related adverse events (irAEs). Two cases of adrenocortical insufficiency have been experienced in Japanese investigational drug trials against NSCLC, but the details have not yet been published. No such cases have been reported in global clinical trials. This is the first case report of ACTH deficiency associated with secondary adrenocortical insufficiency induced by nivolumab in practical use for metastatic NSCLC. Case. A 65-year-old man with stage IIIB lung squamous cell carcinoma was treated with nivolumab as second-line therapy. After 12 cycles of nivolumab, the patient developed appetite loss, general fatigue, low blood pressure and body weight loss. These symptoms were strongly suggested to be related to adrenocortical insufficiency. Endocrinological examinations suggested isolated ACTH deficiency. The symptoms of appetite loss and general fatigue were improved, and the blood pressure was normalized soon after the initiation of treatment with prednisolone. Two weeks later, the performance status (PS) dramatically improved when the patient was discharged. Conclusion. This is the first report of nivolumab-induced ACTH deficiency associated with secondary adrenocortical insufficiency demonstrated by endocrinological tests in practical use for metastatic NSCLC. irAEs, which are associated with immune checkpoint inhibitors, vary in presentation and can be difficult to diagnose. Such events should be carefully checked for in order to ensure their timely management. It may be wise to perform blood biochemical examinations at baseline and before the administration of each nivolumab dose.